PROJECT SUMMARY ABSTRACT Our goal is to continue the Intermountain West Clinical Center for the Childhood Liver Disease Research Network (ChiLDReN) at the University of Utah and Primary Children's Hospital. During the previous funding cycle, we enrolled and retained a significant number of participants, achieved outstanding site performance, and participated in a highly collaborative manner in all Network activities. Additionally, during the previous funding cycle, we transferred, aligned, and processed DNA sequences in support of all Network genomics efforts, and provided the infrastructure to share these sequence data with Network investigators via web- based, password protected software tools. In Aim 1, we will continue to enroll infants, children, and adolescents in current and future ChiLDReN protocols, continue to submit valuable biological specimens and accurate and timely data, and collaboratively participate in all Network activities. In Aim 2, we propose to test the feasibility of a biliary atresia newborn screening program in a large integrated healthcare system covering ~30,000 deliveries per year. All newborns in this healthcare system already undergo total serum bilirubin screening as part of standard of care. We will embed a pilot study in Aim 2 to measure the impact on mothers of newborns with a false positive newborn screen using a case-control repeated measures study design. In Aim 3, we will perform whole genome sequencing on 10 participants and their parents in whom exome sequencing failed to identify a molecular diagnosis. For this Aim, Network investigators will collaboratively select subjects for whole genome sequencing using University of Utah-developed web-based tools. These tools require no bioinformatic expertise and enable expert, Network-wide central genome review. Accomplishing the proposed aims as a highly collaborative Center for ChiLDReN will lead to new knowledge regarding the biochemistry, physiology, and mechanisms of childhood liver diseases, and improve the diagnostic and management options for children afflicted with them.